Oral fluoropyrimidine may augment the efficacy of aromatase inhibitor via the down-regulation of estrogen receptor in estrogen-responsive breast cancer xenografts
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Mamoru Nukatsuka Hitoshi Saito Fumio Nakagawa Masaaki Abe Junji Uchida Jiro Shibata Ken-ichi Matsuo Shinzaburo Noguchi Mamoru Kiniwa
- چاپ و سال / کشور: 2010
Description
The present preclinical study was designed to evaluate a new combination therapy comprised of the aromatase inhibitor anastrozole (ANA) and the oral fluoropyrimidines, UFT and S-1 against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7/Arom 14, which was stably transfected with the cDNA of human aromatase. MCF-7/Arom 14 cells showed a high aromatase activity and notably were able to grow in the presence of testosterone and estradiol (E2) in vitro. ANA and 5-fluorouracil (5-FU) inhibited cell growth at concentrations of 0.005–10 and 0.2–5 lM, respectively, and the combination of both drugs additively inhibited cell growth. The growth of MCF-7/Arom 14 tumors was significantly inhibited by ANA and S-1 or UFT in vivo. The combination of ANA with S-1 or UFT administered using a 21-day consecutive, metronomic-like regimen significantly enhanced the antitumor efficacy, suppressing tumor growth for 2–4 times longer than monotherapy. To investigate the mechanisms by which S-1 enhances the antitumor activity of ANA, the protein and mRNA expression levels of ER-a in tumor tissue after treatment with S-1, ANA, and the typical chemotherapeutic agents doxorubicin (ADM) or paclitaxel (TXL) were analyzed. The protein and mRNA expression levels of ER-a in the tumor tissue were markedly decreased after treatment with S-1 or S-1 ? ANA, but not after treatment with either ADM or TXL. The reduced ER-a level after S-1 treatment might contribute to the increased antitumor activity of ANA by reducing ER-a-induced growth signaling in addition to the decrease in estrogen production induced by ANA. Based on these results, the combination of ANA and S-1 might yield a greater benefit than other chemotherapeutic agents in postmenopausal women with ER-positive breast cancer.
Breast Cancer Res Treat (2011) 128:381–390 Received: 20 April 2010 / Accepted: 18 August 2010 / Published online: 31 August 2010 Springer Science+Business Media, LLC. 2010
